Macrophage/monocyte recruitment plays a role in the morbidity and mortality of a broad spectrum of diseases, including autoimmune diseases, granulomatous diseases, allergic diseases, infectious diseases, osteoporosis and coronary artery disease. For example, in atherosclerosis early during lipid lesion formation, circulating monocytes adhere to the activated endothelium overlying the incipient plaque. Under appropriate conditions, the monocytes then migrate into the developing intima. In the intima, macrophage accumulate lipoprotein and excrete an excess of proteases relative to protease inhibitors. If the lipoproteins are oxidized, they are toxic to macrophage, which results in macrophage death and an increase in an unstable, necrotic, extracellular lipid pool. An excess of proteases results in loss of extracellular matrix and destabilization of the fibrous plaque. Plaque instability is the acute cause of myocardial infarction.
Many molecules have been identified that are necessary for the recruitment of monocytes and other inflammatory cell types. These molecules represent targets for the inhibition of monocyte recruitment. One class of such molecules is adhesion molecules, e.g., receptors, for monocytes. Another class of molecules includes inflammatory mediators, such as TNF-α and related molecules, the interleukins, e.g., IL-1β, and chemokines, e.g., monocyte chemoattractant protein-1 (MCP-1). As a result, agents which modulate the activity of chemokines are likely to be useful to prevent and treat a wide range of diseases. For example, Rollins et al. (U.S. Pat. No. 5,459,128) generally disclose analogs of MCP-1 that inhibit the monocyte chemoattractant activity of endogenous MCP-1. Analogs that are effective to inhibit endogenous MCP-1 are disclosed as analogs which are modified at 28-tyrosine, 24-arginine, 3-aspartate and/or in amino acids between residues 2–8 of MCP-1. In particular, Rollins et al. state that “[s]uccessful inhibition of the activity is found where MCP-1 is modified in one or more of the following ways: a) the 28-tyrosine is substituted by aspartate, b) the 24-arginine is substituted by phenylalanine, c) the 3-aspartate is substituted by alanine, and/or d) the 2–8 amino acid sequence is deleted” (col. 1, lines 49–54). The deletion of amino acids 2–8 of MCP-1 (“MCP-1(Δ2–8)”) results in a polypeptide that is inactive, i.e., MCP-1 (Δ2–8) is not a chemoattractant (col. 5, lines 22–23). The only effective MCP-1 inhibitor disclosed in Rollins et al. is MCP-1 (Δ2–8).
Recent studies suggest that MCP-1 (Δ2–8) exhibits a dominant negative effect, i.e., it forms heterodimers with wild-type MCP-1 that cannot elicit a biological effect (Zhang et al., J. Biol. Chem., 269, 15918 (1994); Zhang et al., Mol. Cell. Biol., 15, 4851 (1995)). Thus, MCP-1 (Δ2–8) does not exhibit properties of a classic receptor antagonist. Moreover, MCP-1 (Δ2–8) is unlikely to be widely useful for inhibition of MCP-1 activity in vivo, as MCP-1 (Δ2–8) is a large polypeptide with undesirable pharmacodynamic properties. Furthermore, it is unknown whether MCP-1 (Δ2–8) is active as a dominant-negative inhibitor of other chemokines associated with inflammation.
Thus, there is a need to identify agents that inhibit or enhance chemokine-induced macrophage and/or monocyte recruitment and which have desirable pharmacodynamic properties. Moreover, there is a need to identify agents that inhibit or enhance chemokine-induced activities of other cell types, such as lymphocytes. Further, there is a need to identify agents that are pan-selective chemokine inhibitors.